Procedural sedation and analgesia versus general anesthesia for hysteroscopic myomectomy (PROSECCO trial): A multicenter randomized controlled trial

Background Hysteroscopic resection is the first-choice treatment for symptomatic type 0 and 1 fibroids. Traditionally, this was performed under general anesthesia. Over the last decade, surgical procedures are increasingly being performed in an outpatient setting under procedural sedation and analgesia. However, studies evaluating safety and effectiveness of hysteroscopic myomectomy under procedural sedation are lacking. This study aims to investigate whether hysteroscopic myomectomy under procedural sedation and analgesia with propofol is noninferior to hysteroscopic myomectomy under general anesthesia. Methods and findings This was a multicenter, randomized controlled noninferiority trial conducted in 14 university and teaching hospitals in the Netherlands between 2016 and 2021. Inclusion criteria were age ≥18 years, maximum number of 3 type 0 or 1 fibroids, maximum fibroid diameter 3.5 cm, American Society of Anesthesiologists class 1 or 2, and having sufficient knowledge of the Dutch or English language. Women with clotting disorders or with severe anemia (Hb < 5.0 mmol/L) were excluded. Women were randomized using block randomization with variable block sizes of 2, 4, and 6, between hysteroscopic myomectomy under procedural sedation and analgesia (PSA) with propofol or under general anesthesia (GA). Primary outcome was the percentage of complete resections, assessed on transvaginal ultrasonography 6 weeks postoperatively by a sonographer blinded for the treatment arm and surgical outcome. Secondary outcomes were the surgeon’s judgment of completeness of procedure, menstrual blood loss, uterine fibroid related and general quality of life, pain, recovery, hospitalization, complications, and surgical reinterventions. Follow-up period was 1 year. The risk difference between both treatment arms was estimated, and a Farrington–Manning test was used to determine the p-value for noninferiority (noninferiority margin 7.5% of incomplete resections). Data were analyzed according to the intention-to-treat principle, including a per-protocol analysis for the primary outcome. A total of 209 women participated in the study and underwent hysteroscopic myomectomy with PSA (n = 106) or GA (n = 103). Mean age was 45.1 [SD 6.4] years in the PSA group versus 45.0 [7.7] years in the GA group. For 98/106 women in the PSA group and 89/103 women in the GA group, data were available for analysis of the primary outcome. Hysteroscopic resection was complete in 86/98 women (87.8%) in the PSA group and 79/89 women (88.8%) in the GA group (risk difference −1.01%; 95% confidence interval (CI) −10.36 to 8.34; noninferiority, P = 0.09). No serious anesthesiologic complications occurred, and conversion from PSA to GA was not required. During the follow-up period, 15 serious adverse events occurred (overnight admissions). All were unrelated to the intervention studied. Main limitations were the choice of primary outcome and the fact that our study proved to be underpowered. Conclusions Noninferiority of PSA for completeness of resection was not shown, though there were no significant differences in clinical outcomes and quality of life. In this study, hysteroscopic myomectomy for type 0 and 1 fibroids with PSA compared to GA was safe and led to shorter hospitalization. These results can be used for counseling patients by gynecologists and anesthesiologists. Based on these findings, we suggest that hysteroscopic myomectomies can be performed under PSA in an outpatient setting. Trial registration The study was registered prospectively in the Dutch Trial Register (NTR 5357; registration date: 11 August 2015; Date of initial participant enrollment: 18 February 2016).

Questionnaire on side effects 24 hours after hysteroscopic myomectomy (English Version)

No pain Worst pain you can imagine
No nausea

Questionnaire for evaluation of recurrence after hysteroscopic myomectomy (English version)
It has been a year since you underwent the hysteroscopic myomectomy (the removal of a fibroid with a small instrument through the vagina).We would like to know if you experienced a recurrence of your fibroid and whether or not you underwent treatment for this during the last year.To evaluate this, please answer the following questions by checking the appropriate box.

Changes compared to previous version
The current version is the second version.

Introduction
Hysteroscopic myomectomies are performed in the majority of Dutch hospitals.The number of procedures for submucosal type 0 or I myomas between 1-3 cm performed in the operating room is estimated to be 3000 per year.Hysteroscopic myomectomy was traditionally performed in day treatment under general anesthesia.(1)A considerable cost reduction is expected when procedural sedation (PSA) is applied.The major contributing factors to the cost reduction are the shift from surgery in an operating theatre to an office-based setting, shorter hospital stay and outpatient care versus day care.(2,3)Higher patient satisfaction is expected, as hospital stay is shorter and side effects such as nausea are reduced.However, both safety and effectivenessincluding the necessity for reintervention due to incomplete resectionhave not yet been fully evaluated.

Primary objective
To assess the non-inferiority in effectiveness of hysteroscopic resection of submucous myomas under procedural sedation with propofol (PSA) in an outpatient setting as compared to hysteroscopic myomectomy performed under general anesthesia in the operating room.

Secondary objectives
Secondary, completeness of resection as judged by the surgeon, pain, return to daily activities/recovery, duration of hospitalisation, (post)operative complications, the need for surgical reinterventions, menstrual blood loss (PBAC score), quality of life and uterine fibroids symptoms and related quality of life will be investigated.In addition, economic analyses (cost-effectiveness) will be conducted, being outside the scope of this Statistical Analysis Plan.

Study population
Women 18 years or older, with a maximum of 3 symptomatic type 0 or I submucous myomas with a maximum diameter of 3.5 cm.They must be classified as American Society of Anesthesiologists class 1 or 2, and comprehension of the Dutch or English language to fully understand the study and to complete the questionnaires.

Inclusion criteria:
In order to be eligible to participate in this study, a subject must meet all of the following criteria: -Minimum age of 18 years; -Symptomatic type 0 or I submucous myomas -Maximum number of submucous myomas of 3 -Maximum diameter of submucous myomas of 3.5 cm (as diagnosed by transvaginal ultrasonography) -American Society of Anesthesiologist class 1 or 2

Exclusion criteria
The following exclusion criteria are used: -American Society of Anesthesiologists class 3 or 4 -Presence of clotting disorders -Severe anaemia (Hb under 5.0 mmol/L) -Inability to understand Dutch or English

Study design
The study is designed as a multicentre open-label randomised controlled clinical trial to investigate non-inferiority of procedural sedation and analgesia with propofol as compared to general anesthesia.

Randomisation and masking
Randomisation is done using TEN/ALEA in a 1 : 1 ratio with variable block sizes of 2, 4, or 6, and is stratified by the surgical technique used (either morcellation or resection).
Healthcare providers and patients are not blinded.
The gynaecologist or ultrasonographer performing the transvaginal ultrasound 6 weeks after surgery will be blinded for the surgery outcome.

Treatment of subjects
Hysteroscopic resection is performed by an experienced surgeon by standard procedure in an office-based setting.Patients are observed after the procedure by qualified personnel and discharged as soon as all the discharge criteria are met, normally within 1 to 1.5 hours.
The way hysteroscopic resection is performed under general anesthesia does not differ from the way it is performed under procedural sedation.

Procedural sedation and analgesia
Patients randomised to procedural sedation and analgesia will receive propofol combined with alfentanil or remifentanil.Sedation is given and monitored by a qualified sedation practitioner, according to guidelines from the Health Care Inspectorate (IGJ) and Dutch Institute for Healthcare Improvement (CBO) Non-Anesthesiologist Administered Propofol (NAAP).(4,5)The patient will be assessed by the sedation practitioner immediately prior to surgery on the basis of a preoperative questionnaire.Non-invasive blood pressure, electrocardiogram and oxygen saturation are measured before vascular access is obtained.

General anesthesia
General anesthesia can be inhalational or total intravenously, with the use of a laryngeal mask.Postoperatively, patients will be observed in the recovery room and discharged home from the clinic when all the discharge criteria are met.

Endpoints 10.1
Primary endpoint Percentage of complete resections, as evaluated using transvaginal ultrasonography (TVU) (contrast sonography if TVU is inconclusive) six weeks postoperatively by an independent gynaecologist or ultrasonographer blinded for the treatment arm and surgery outcome.
A complete resection means that there are no signs of an intracavitary remaining of the fibroid (s) resected during hysteroscopic myomectomy.When resection is concluded to be incomplete based on the TVU, the images will be adjudicated by an independent review committee.When applicable the result of the TVU will be recorded as complete after adjudication.

10.2
Secondary endpoint -Completeness of resection as judged by the surgeon during the procedure -Pain (NRS score) when awake after the procedure and at discharge as recorded in the Case Record Form (CRF) and at 24 hours of follow-up as measured through a self-tailored questionnaire (supplementary file) -Return to daily activities/recovery at 24 hours, 2 weeks and 8 weeks of follow-up as measured through the Recovery Index Questionnaire(6) -Duration of hospitalisation in minutes as recorded in the CRF -Peri-and postoperative complications until 6 weeks follow-up as recorded in the CRF -The need for surgical re-interventions at 12 months follow-up as recorded in the CRF and measured through a self-tailored questionnaire (supplementary file)

10.3
Other outcomes -Menstrual blood loss at baseline, 8 weeks and 12 months follow-up as measured through PBAC scores(7) -Quality of life at baseline, 24 hours, 2 weeks, 8 weeks, 6 months, 12 months, as measured through the EQ-5D-5L questionnaire(8) -Uterine fibroids symptoms and related quality of life at baseline and 8 weeks follow-up as measured through the UFS-QoL questionnaire(9,10)

Sample size and non-inferiority margin
The incidence of incomplete resections is estimated as 2.5% in both treatment groups based on expert opinion and previous literature.(11-13)An upper limit of the non-inferiority margin at 10% incomplete resections (i.e. a delta of 7.5%) is considered to represent noninferiority sufficiently.If alpha is chosen as 0.025 then a total sample size of 186 achieves 90% power.Allowing for a drop-out due to loss to follow-up of 10%, then 206 need to be recruited into the trial.
The sample size does not require adjustment for multiple testing, and interim analyses for efficacy are not conducted.

General outline of analyses 12.1 Trial profile
The flow of study participants will be displayed in a CONSORT diagram (Figure 1).

Full Analysis population (ITT)
The Intention-To-Treat (ITT) populations will consist of all patients who have given consent and have been allocated one of the two treatments, irrespective of treatment received.

Per-protocol population
Secondary to the intention-to-treat population, the primary outcome will also be investigated using the per-protocol population.
The per protocol population is defined as any patient who underwent myomectomy with general anesthesia or procedural sedation as allocated using randomisation.Patients who did not have myomectomy or who did not receive the type of anesthesia allocated by randomisation will be removed from the per-protocol population.

Planned analyses 13.1.1 Baseline characteristics
Baseline characteristics and characteristics of surgical procedure and anesthesia will be presented as numbers and percentages in each group, or as averages (mean or median) with standard deviations or interquartile ranges as appropriate.Relative risks will be given for surgical characteristics where applicable (Table 1,2).

Primary outcome
The primary outcome is complete myoma resection as determined using transvaginal ultrasonography six weeks after myomectomy.The primary outcome will be evaluated by estimating the risk difference between both treatment arms.A Farrington-Manning test will be used to determine the p-value for non-inferiority.Analyses will be conducted on both the intention-to-treat, as well as the per-protocol populations for the primary outcome (Table 3).

Secondary outcomes
Frequencies and relative risks for the surgeon's judgement on completeness of resection will be presented (Table 4).The types, frequencies and relative risks for (post)operative complications will be given (Table 5-7).Descriptive statistics on the duration of hospitalisation will be presented in table 8.The types, frequencies and relative risks for surgical re-interventions after 12 months of follow-up will be given (Table 9) Recovery Index scores at 24 hours, 2 weeks and 8 weeks and NRS scores for pain intensity after the procedure when awake, at discharge and at 24 hours will be reported as means with SD, or medians with IQR as appropriate, risk differences between both groups will be calculated with according 95% confidence interval (Table 10 and 11).

Other outcomes
PBAC scores at baseline, 8 weeks and 12 months will be analysed longitudinally using a generalized estimating equations model for repeated measures (Table 12).UFS-QoL scores at baseline and 8 weeks and EQ-5D-5L mean total score and VAS scores at baseline, 24 hours, 2 weeks, 8 weeks, 6 months and 12 months are presented in table 13 and table 14.Differences in median between groups and changes from baseline within groups will be provided.

Statistical analysis
Relative risks will be estimated for categorical outcomes, with 95% confidence intervals, and χ 2 tests for significance.Fisher's exact test will be used for sparse events where assumptions of the χ 2 test are not met.Continuous data will be described as means with standard deviation if normally distributed, or medians with interquartile ranges when not normally distributed data; tests for significance are ttests or Mann-Whitney U tests, respectively.The Hodges-Lehman estimator will be used to calculate the confidence interval for the difference in medians.A sign test for within group change from baseline will be used.The PBAC scores will be analyzed longitudinally using generalized estimating equations.

13.2
Covariates and subgroups 13.2.1 Covariates No analyses are planned for which estimates will be adjusted for effects of covariables other than the stratification factor (resection technique).We will also calculate the relative risk, adjusted for the resection technique which was used.)

Subgroups
Analyses for the primary outcome will be performed by resection technique (resection or morcellation. We will perform a subgroup analysis for fibroid size (< 2 cm versus ≥2 cm) and for parity (nulliparous versus multiparous women).

Missing data
The primary outcome is assessed six weeks after surgery, and much missing data for the primary outcome is not to be expected.However, drop-out has been allowed for in the sample size and a complete case analysis will be used if outcomes are missing.Imputation for missing data will not be used.

Interim-analysis and data monitoring
No interim analysis for efficacy will be conducted.
The DSMB charter of the study specifies interim safety review to be done after outcome data is available for every 50 participants.The DSMB may decide to alter the frequency of these safety reviews as needed.

Multiple testing
Given that interim analyses for efficacy are not conducted, correction for multiplicity of testing is considered not to be required.Subgroup analyses will be done for parity and myoma size.These subgroup analyses will be exploratory.Adjustment of the p-value will not be done.

3 . 4 .
Did you have to throw up after the surgery?Yes □ No □ Did you check yes?Go to question 4. Otherwise skip to question 5. How many times did you have to throw up after the surgery?…………………..times 5. How much pain do you experience at the moment?At this scale, please mark the number that indicates how much pain you experience at the moment.'0' means you don't experience any pain, '10' means the most extreme pain you can imagine.

Table A . Surgical and anesthesia details
Supplementary table A |Surgical and anesthesia details.IQR: Interquartile Range.Percentages are column percentages based on the number of observations available (i.e.excluding missing observations).Relative risks with 95% confidence intervals and Chi-squared test.* Fisher's exact test.† Difference in median with Hodges-Lehmann estimator and p-value for Mann-Whitney test.

Table B . Subgroup analyses for primary outcome Intention-to-treat Per protocol
Supplementary table B | Subgroup analyses.PSA: Procedural sedation and analgesia, GA: general anesthesia, CI: confidence interval.Results of subgroup analyses are subject to confounding and multiple testing and should be interpreted with caution.P-values for interaction of treatment effect and sub-group.

Table C . Surgeon's judgement on completeness and ease of procedure
Supplementary table C | Surgeon's judgement on completeness and ease of procedure.PSA: Procedural sedation and analgesia, GA: General anesthesia.Percentages are column percentages based on the number of observations available (i.e.excluding missing observations).*multipleanswers can apply.

NRS score at return in recovery room, discharge and 24 hours follow-up.
NRS: Numeric Rating Scale.PSA: Procedural sedation and analgesia, GA: General anesthesia.

Supplementary table H | PBAC score at baseline, 8 weeks, 12 months follow-up. Medians
and interquartile ranges.PBAC: Pictorial Blood Assessment Chart, PSA: Procedural sedation and analgesia, GA: General anesthesia.Sign test for within group change from baseline.Difference in median difference from baseline between groups with Hodges-Lehman estimator with p-value for Mann-Whitney test.*Overall estimate is mean difference over all time points with a Poisson distribution using a GEE repeated measures model including variables adjusting for baseline score, time and interaction of treatment effect and time.

Uterine Fibroid Symptom-Quality of Life questionnaire at baseline and 8 weeks follow-up.
SSS: Symptom Severity Scale.HRQL: Health Related Quality of Life scale.PSA: Procedural sedation and analgesia, GA: General anesthesia.Medians with interquartile ranges, Hodges-Lehmann estimator for difference in median between groups with p-value for Mann-Whitney test.Sign-test for within group change from baseline Appendix 3.

Table 1 |
Baseline characteristics.Sd: standard deviation, IUD: intrauterine device, GnRH: gonadotropinreleasing hormone.Percentages are column percentages based on the number of observations available (i.e.excluding missing observations).

Table 2 | Surgical procedure and anesthesia. IQR
: Interquartile Range, sd: standard deviation.Percentages are column percentages based on the number of observations available (i.e.excluding missing observations).* Mean difference and p-value for t-test † Difference in median with Hodges-Lehmann estimator and p-value for Mann-Whitney test.

Table 3| Completeness of resection based on transvaginal ultrasound 6 weeks after hysteroscopic myomectomy
. IQR: Interquartile Range.Percentages are column percentages based on the number of observations available (i.e.excluding missing observations).* Difference in median (Hodges-Lehman), with p-value from Mann-Whitney test.

Table 4 | Surgeon's judgement on completeness of procedure.
Percentages are column percentages based on the number of observations available (i.e.excluding missing observations).

Table 5 |
Surgical complications.Percentages are column percentages based on the number of observations available (i.e.excluding missing observations).

Table 6 |
Anesthetic complications.Percentages are column percentages based on the number of observations available (i.e.excluding missing observations).

Table 7 | Follow-up visit six weeks after surgery.
Percentages are column percentages based on the number of observations available (i.e.excluding missing observations).

Table 8 |
Hospitalisation IQR: Interquartile Range.Percentages are column percentages based on the number of observations available (i.e.excluding missing observations).* Mean difference and p-value for t-test

Table 9 | Surgical reinterventions 12 months after surgery.
Percentages are column percentages based on the number of observations available.

Table 10 | RI10 score at 24 hours, 2 weeks and 8 weeks follow-up. RI10
: Recovery Index Questionnaire.PSA: Procedural sedation and analgesia, GA: general anesthesia.Medians with interquartile ranges.Hodges-Lehmann estimator for difference in median between groups with p-value for Mann-Whitney test.

Table 11 | NRS score at return in recovery room, discharge and 24 hours follow-up
. NRS: Numeric Rating Scale.PSA: Procedural sedation and analgesia, GA: General anesthesia.Medians with interquartile ranges.Hodges-Lehmann estimator for difference in median between groups with p-value for Mann-Whitney test.

Table 12 | PBAC score at baseline, 8 weeks, 12 months follow-up
. PBAC: Pictorial Blood Assessment Chart.*Overall estimate is mean difference over all time points using a repeated measures model including variables adjusting for group, baseline score and time.

Table 13 | Uterine Fibroid Symptom-Quality of Life questionnaire at baseline and 8 weeks follow-up
. SSS: Symptom Severity Scale.HRQL: Health Related Quality of Life scale.PSA: Procedural sedation and analgesia, GA: General anesthesia.Medians with interquartile ranges, Hodges-Lehmann estimator for difference in median between groups with p-value for Mann-Whitney test.Sign-test for within group change from baseline.